Supplementary Material
Clinical Details
A:II:1
Previously reported in the literature to carry a LMNA/C mutation (Patient 6 in Am J
Med Genet 2008). He was found to carry a missense mutation in LMNA
(p.Arg644Cys) reported to be associated with an extremely variable clinical
phenotype (Fig 3). No early childhood or developmental problems. A good but not
exceptional sportsman – playing for the school rugby and cricket teams. On leaving
school he worked as a labourer. Not aware of any problems until his early 50’s when
he started to have difficulty carrying very heavy equipment and was not able to lift
objects over his head. By his late 50’s he started to have problems rising from a low
chair, having noticed increasing difficulty with stairs for a couple of years prior to
that. He had never been able to whistle or blow up balloons, and had a tendency for
soap to get in his eyes. On examination at 66 years, he had mild facial weakness,
bilateral pectoral creases, marked wasting of biceps and triceps and a protuberant
abdomen. There was bilateral scapular winging. He had symmetrical proximal
weakness of the lower leg muscles – worst at 4/5 for hip flexion and knee flexion and
extension. Upper limb weakness was more pronounced and asymmetrical the right
being worse – grade 2/5 elbow flexion and extension (left 3/5 for both). Weakness
extended to the wrists, but pinch strength was normal. He could only abduct his arms
to 45° bilaterally. Beevor’s sign was positive. There was no evidence of
lipodystrophy. No knee contractures, 20° of contracture at the left elbow, minimal at
the right. An ECG showed first degree heart block with a PR interval of 204 ms, but
otherwise a full cardiological assessment including echocardiogram was normal.
Assessment 4 years later showed only slight progression – the most noticeable of
which was a right footdrop. Hand-grip dynamometry gave maximum values of 11.6
KgF on the right and 19.6 KgF on the left.
A:II:2
Individual A:II:2 was assessed at 64 years in order to establish the clinical
significance of a LMNA missense mutation that had been identified in II.1. Childhood
milestones had been normal and she had been a fast runner, the fastest amongst her
peers. She recalled starting to have falls due to her knees giving way from about 16
years of age. She experienced aching in her legs and increasing difficulty managing
stairs. Clinical examination in her 3rd pregnancy at 24 years of age showed marked
“enfeeblement” of the right biceps and of the distal quadriceps bilaterally. Mild pes
cavus was noted. She was diagnosed with Erb’s juvenile dystrophy (scapulohumeral
muscular dystrophy). There was very little progression of her condition. By 27 years
she continued to have difficulty walking, climbing stairs, holding her children or
brushing her hair. Examination revealed asymmetric proximal wasting and weakness
of the thighs (R > L) and of the right arm and forearm, and CPK 87 IU/L. The
diagnosis was reconsidered because of “bottleshaped” wasting of the distal thighs
with pes cavus and the diagnosis changed to peroneal muscular atrophy. Further
clinical review at 29 years reported asymmetric onset of weakness in both arms, 18
months before the development of asymmetric weakness in both legs, left greater than
the right. EMG and muscle biopsy at 29 years were each compatible with a myopathy
and the diagnosis reverted to that of limb-girdle muscular dystrophy.
At 56 years she was admitted with a non-ST elevation myocardial infarct with a raised
troponin-T of 0.12 U/L. ECG showed “very marked first degree heart block”. The
troponin-T continued to be slightly elevated at 0.11 U/L. Coronary angiography
showed “surprisingly” normal coronary arteries. But she went into atrial flutter and
subsequently required DC cardioversion and a permanent pacemaker inserted. There
was no evidence of cardiomyopathy.
She became a lot weaker from the late 50’s, first starting to use a wheelchair out-ofdoors from 60 years. She had never been able to blow up balloons, but could whistle.
She did not sleep with her eyes open. At 63 years she had a CVA with nominal
aphasia.
Examination at 64 years was complicated by a recovering right-hemiplegia. She had
a flat mid-face with paucity of movement bilaterally. Her lips were large and full with
an asymmetric smile, the righter weaker, and a fair left pucker. The left upper limb
distal strength especially the hand and wrist were normal, with weakness of elbow
flexion and extension. There was winging of the scapula; abduction of the shoulder to
45o. In the lower limb there was proximal weakness of the left hip (4-), knee flexion
and extension (2 and 3), ankle dorsiflexion and plantarflexion (3 and 4). There were
contractures at the elbows - right 30o, left 20o; and right knee 20o. There was no pes
cavus.
The diagnosis of autosomal dominant Emery-Dreifuss muscular dystrophy was
considered because of her own and her brother’s contractures together with her
history of cardiac dysrhythmia and pacemaker insertion. She does not carry the LMNA
variant. Clinically her phenotype is that of later onset FSHD, originally diagnosed in
1970 as Erb’s juvenile muscular dystrophy (scapulohumeral muscular dystrophy).
A:III:1
No early childhood problems, a member of the school cross-country and netball
teams. She had no problems with ladders, stairs or low chairs. Could whistle, blow up
balloons and did not sleep with her eyes open. On examination at 42 years she could
bury her eye-lashes deeply and could whistle. She could achieve full elevation of both
arms, had no difficulty rising from a low chair with her arms folded and could walk
on tip-toe and her heels with ease. Hand-grip dynamometry gave maximum values of
22.8 and 19.6 kgF respectively for the right and left hands. She was adjudged to be
clinically unaffected or presymptomatic.
A:III:2
Early childhood and development normal. Not the fastest at running, no difficulty
climbing ropes or doing push-ups. First became aware of difficulty holding a hawk on
his abducted arm at 34 years. With hindsight he felt he had always had poorly
developed upper arms, and his girl-friend had previously noted his “chicken-wings” in
his mid-20s. There were no functional problems with his legs – managing stairs,
ladders, low chairs with no difficulty. He had never been able to whistle but could
suck and did not sleep with his eyes open. On examination at 37 years he had subtle
weakness of eye closure, the lower limbus of the sclera being visible, but otherwise
could bury his eye-lashes. He had an asymmetric smile with flat horizontal lips but
normal cheek puff. There was marked asymmetric wasting of the upper arms
especially of the left biceps and triceps with relative sparing of the deltoid and
asymmetric bilateral pectoral creases (right worse than left). He could abduct his arms
to 60° and 55°, achieving full elevation on manual fixation of the scapula. Biceps and
triceps were very weak on the left (2 and 3 on MRC grades) compared to 4- for both
on the right. Distal strength in the wrists and hands was normal as were all
assessments in the lower limb apart from mild weakness of knee extension. He had a
positive Beevor’s sign. He could rise from a chair with his arms folded and walk on
tip-toe and his heels with ease. Re-examination at 41 years was essentially unchanged
except that the weakness of biceps had progressed to grade 1/5. Shoulder abduction
was unchanged. Hand-grip dynamometry gave maximum values of 31.3 and 27.4 kgF
for the right and left hands respectively. There were no contractures. ECG and
echocardiography were unremarkable.
Family B
B:II:1 and B:II:2
Neither sister reports any clinical problem. Examination at 61 and 56 years
respectively was completely normal
B:II:3 (proband)
Originally referred at 41 years because of a history suggestive of connective tissue
problems with a “Marfanoid” appearance, the features included recurrent knee
dislocations (from age 7), short stature, joint hypermobility myopathic facies and a
high arched palate (Fig 4). There was no family history of ocular or cardiac anomalies
seen in Marfan Syndrome. Marfan syndrome was excluded clinically, including
normal ophthalmic and cardiac assessments. Examination at 42 years: weakness of
eye closure with difficulty burying the eyelashes was noted. There was no weakness
of proximal or distal muscles in the upper limb. There was mild weakness of hip
flexion and ankle eversion, with bilateral pes cavus and clawing of the toes. NCV
were normal, EMG demonstrated no abnormality, facial EMG was not tolerated. A
muscle biopsy (left quadriceps) showed no evidence of inflammation, dennervation or
of muscular dystrophy. Over the years she has slowly deteriorated with predominantly
distal upper-limb weakness and proximal lower-limb weakness. However she remains
ambulant for short distances. Cranial and spine MRI have been normal. The clinical
phenotype is unusual and no diagnosis has been made. DM2, HMSN1A and FSHD
have all been tested although none of these was ever considered a strong candidate,
but testing undertaken to exclude them as a potential confounder.
B:II:4
The younger sister of II:3 has not been examined but is reported by the family to have
similar problems with her feet and a very similar facial appearance to her sister with
paucity of movement of the mid face and upper lip with weakness of eye closure.
Photographs shown to (MTR) support this assertion.